tbuckley/cabot-search huggingface dataset:
Abstract 2675: Vactosertib combined treatment with T1-44, a PRMT5 activity inhibitor, improves the survival and inhibits tumor invasion of murine pancreatic cancer model
Authors: Eunji Hong, Sujin Park, Seok Hee Park, Nick B. La Thangue, Seong-Jin Kim
Journal: Cancer Research (2023)

Abstract Pancreatic cancer is the most lethal type of cancer and the third leading cause of cancer death with the lowest 5-year survival rate. Heterogeneity, difficulty in diagnosis, and rapid metastatic progression are the causes of high mortality in pancreatic cancer. Recent studies have shown that Protein arginine methyltransferase 5 (PRMT5) is overexpressed in pancreatic cancers, and these patients have a worse prognosis. Therefore, PRMT5 as an anti-cancer target has gained considerable interest. In this study, we investigated whether inhibition of PRMT5 activity was synergistic with blockade of TGF-β1 signaling, which plays an important role in the construction of the desmoplastic matrix and invasiveness in pancreatic cancer and induces therapeutic vulnerability. Compared with T1-44, a selective inhibitor of PRMT5 activity, the combination of T1-44 with the TGF-β1 signaling inhibitor vactosertib significantly reduced tumor size and surrounding tissue invasion and significantly improved long-term survival. RNA sequencing analysis of mouse tumors revealed that the combination of T1-44 and vactosertib significantly altered the expression of genes involved in cancer progression, such as cell migration, extracellular matrix, and apoptotic processes. These data demonstrate that the combination therapy of T1-44 with vactosertib is synergistic for pancreatic cancer, suggesting that this novel combination therapy has value in the treatment strategy of patients with pancreatic cancer. Citation Format: Eunji Hong, Sujin Park, Seok Hee Park, Nick B. La Thangue, Seong-Jin Kim. Vactosertib combined treatment with T1-44, a PRMT5 activity inhibitor, improves the survival and inhibits tumor invasion of murine pancreatic cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2675.
Abstract 4404: Survival impact and trends of immunotherapy use in metastatic merkel cell carcinoma in the checkpoint era: analysis of a large database
Authors: Christopher R. Grant, Garo Hagopian, Danielle Brazel, Priyanka Kumar, Justin Moyers
Journal: Cancer Research (2023)

Abstract Introduction: Merkel Cell Carcinoma (MCC) is an aggressive skin cancer that has typically been treated with conventional chemotherapy in the metastatic setting. In 2017, metastatic MCC treatment options expanded when the FDA approved immune checkpoint inhibitors based on single-arm uncontrolled studies. We utilized data from the National Cancer Database (NCDB) to examine the survival benefit of first line immunotherapy (IO) or chemotherapy (CT) in metastatic MCC. Methods: The NCDB was analyzed to identify patients with metastatic MCC from 2017-2020. Patients who did not have data available on AJCC version 8 staging group, survival status, and treatment details (surgery, radiation therapy, CT, IO) were excluded from the analysis. Patients were divided into cohorts based on first line systemic therapy; those who received chemotherapy and those who received immunotherapy. Survival time was calculated from the time of initiation of systemic treatment to last contact or death. Overall survival (OS) was estimated by Kaplan-Meier method and compared by log-ranked method. Results: We identified 648 patients with stage IV MCC between 2017-2020. Of those, 15.3% (n=99) received CT, 51.7% (n=335) received IO, and 32.9% (n=213) did not receive systemic therapy. Median OS was 13.2 (95% CI: 10.1-16.2) months for those receiving any systemic therapy. Median OS was 13.8 (95% CI: 7.9-19.7) months for CT and 12.9 (95% CI: 9.6-16.2) months for immunotherapy (p=0.379). In the first year of IO approval in 2017, only 37.4% of patients received IO which increased to 54.5% in 2018, 59.6% in 2019, and 54.9% in 2020. Chemotherapy use decreased throughout the same time period from 23.9% in 2017 to 12.4% in 2020. There was a notable difference in the number of patients less than 65 years old who received IO (66%) relative to the number of patients 65 years and older who received IO (80%) (p=0.006). Discussion: Immunotherapy has supplanted chemotherapy as the first line treatment of choice in MCC, particularly in those 65 and older. However, we did not find first line use of immunotherapy to provide a statistically significant survival advantage over chemotherapy in stage IV Merkel cell carcinoma. Clinical equipoise exists, and a randomized clinical trial is needed. Citation Format: Christopher R. Grant, Garo Hagopian, Danielle Brazel, Priyanka Kumar, Justin Moyers. Survival impact and trends of immunotherapy use in metastatic merkel cell carcinoma in the checkpoint era: analysis of a large database. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4404.
Abstract 4416: IL-1 blockade prevents cardiac toxicity and improves immunotherapy efficacy
Authors: Nilesh P. Talele
Journal: Cancer Research (2023)

Abstract Background: Immune checkpoint blockers (ICBs) have revolutionized cancer treatment, but they are often associated with severe immune related adverse events (irAEs). These severe irAEs are more often seen in patients with obesity or concomitantly treated with cytotoxic therapies. Methods: We aimed to understand the mechanisms of ICB-induced irAEs, in the context of obesity and ICB/chemotherapy combinations. We developed a mouse model of cardiac irAEs, which is the most fatal type of irAE in ICB-treated cancer patients, with clinically relevant features: (i) an ICB-resistant cancer (pancreatic ductal adenocarcinoma or PDAC), (ii) obesity induced with high-fat diets, and (iii) a combination treatment of ICB (α-PD1 + α-CTLA4) and chemotherapy (FOLFIRINOX). Results: Our FDA and single institution retrospective analyses indicate that patients treated with ICB had greater relative risk of developing myocarditis as compared to other anti-cancer therapies. Mice with orthotopic PDAC and obesity developed irAEs after treatment with ICB and chemotherapy as compared to chow diet. These irAEs recapitulated those observed in patients with cancer and obesity, including cardiac dysfunction consistent with myocarditis, cardiac fibrosis, and increased circulating levels of interleukin-1 beta (IL-1b). IL-1β blockade prevented myocarditis and reduced cardiac fibrosis after immunotherapy. Importantly, IL-1β blockade also enhanced the anti-tumor effects of ICB + FOLFIRINOX combination therapy, and increased mouse survival. Conclusions: We developed a translationally relevant 'triple hit' mouse model and discovered that IL-1β mediates ICB-induced cardiotoxicity. In addition, we found that IL-1β blockers, which are already used in the clinic for cardiology indications, both reduce adverse events and simultaneously enhance the antitumor effects triggered by immunotherapy. Citation Format: Nilesh P. Talele. IL-1 blockade prevents cardiac toxicity and improves immunotherapy efficacy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4416.
Abstract 4417: Activity of novel RNA therapeutics to overcome resistance to immune checkpoint blockade
Authors: Marvin O'Ketch, Jeffrey A. Kiefer, Dnyanesh Rasale, Warren S. Weiner, Lizette A. Castaño, Nathalie A. Azorsa, David W. Lee, Kerry M. Barnhart, Spyro Mousses, David O. Azorsa
Journal: Cancer Research (2023)

Abstract T-cells in the tumor microenvironment can often become exhausted and dysfunctional due to chronic and prolonged exposure to antigen. The resulting condition of T cell exhaustion represents an important mechanism of clinical resistance to immune checkpoint blockade. The transcription factor NR4A1 is known to be upregulated in tumor-specific T-cells and is a mediator of T cell dysfunction including driving exhaustion during chronic antigen stimulation of T-cells. Pro-oncogenic activities of NR4A1 have been observed in various solid tumors, including colorectal and breast cancers, and co-expression of NR4A1 with known immune checkpoint markers such as PD-L1 and B7 family members has also been observed in various cancer cell lines. These findings have identified NR4A1 as an important target for overcoming resistance to cancer immunotherapy. We hypothesize that targeted silencing of the NR4A1 and other immunomodulatory genes can reverse T-cell exhaustion and expand the clinical benefit of immune checkpoint blockade in solid tumors resistant to immune therapy. To reverse T-cell exhaustion with a targeted approach, we developed T cell targeting SeekRsTM, which are chimeric RNA therapeutics containing dual-flanking aptamer binders connected by a double-stranded bridge containing siRNA silencers that can target multiple immunomodulatory genes. First-generation aptamer-siRNA chimeras designed with a CTLA-4 targeting aptamer containing a STAT3 siRNA demonstrated effectiveness in silencing its target. Modifications to the structure included the addition of chemically modified nucleotides to improve serum stability. Additionally, dimerization of the structure to form a SeekR dimer molecule greatly improved internalization and target silencing compared to the monomeric chimera. Newly developed SeekRs targeting T cells and designed to silence NR4A1 have effectively downregulated NR4A1 in model cell lines and activated T cells. These results demonstrate that dual targeting SeekRs can be used to specifically deliver siRNA to T cells for targeted silencing that can reverse exhaustion and potentially overcome resistance to cancer immunotherapy in the clinic. Citation Format: Marvin O'Ketch, Jeffrey A. Kiefer, Dnyanesh Rasale, Warren S. Weiner, Lizette A. Castaño, Nathalie A. Azorsa, David W. Lee, Kerry M. Barnhart, Spyro Mousses, David O. Azorsa. Activity of novel RNA therapeutics to overcome resistance to immune checkpoint blockade. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4417.
Abstract 4397: Chemotherapy-induced peripheral neuropathy and falls in cancer survivors relate to digital balance and gait impairments
Authors: Vrutangkumar Shah, Daniel Muzyka, Carolyn Guidarelli, Kristen Sowalsky, Kerri M. Winters-Stone, Fay B. Horak
Journal: Cancer Research (2023)

Abstract Background and Aim: Standing postural sway and gait tests with body-worn inertial sensors provide a multitude of objective, digital balance, and gait measures that represent several different domains controlling mobility. However, it is not clear which domains of balance or gait best reflect the impact of treatment-induced peripheral neuropathy on mobility or differentiate fall risk in cancer survivors. This study aimed to determine which domains of balance and gait differed between cancer survivors who reported 1) symptoms of peripheral neuropathy versus asymptomatic survivors and 2) falls in the previous six months versus non-fallers. Methods: Both postural sway during 30 seconds of quiet stance and gait characteristics from the Instrumented Time-Up-and-Go test (ITUG) were recorded with six synchronous inertial sensors (Opals by APDM Wearable Technology, a Clario company). The sensors were placed on both shanks and wrists, and one on the lumbar spine and sternum in 425 female cancer survivors (age: 62 ± 6 years). A principal component analysis (PCA) approach was used first to identify independent domains of mobility from 14 balance and gait measures for subsequent analysis. Results: PCA analysis revealed 5 independent domains (PC1: Sway amplitude, PC2: Gait pace; PC3: Sway frequency; PC4: Gait spatial-temporal and PC5: Turning) that accounted for 81% of the variance of performance across the participants. Cancer survivors who reported neuropathy showed a significantly higher sway frequency (PC3) than asymptomatic survivors. Cancer survivors who reported falls showed a significantly larger sway area (PC1) and slower gait pace (PC2) than non-fallers. Conclusions: Wearable sensor instrumentation from short balance and gait tests capture objective digital gait and balance outcomes reflective of treatment-related neuropathy and fall risk in women treated with chemotherapy for cancer. Wearable sensors could be used for oncology clinical trials to assess the impact of cancer treatment and symptom mitigation strategies to limit changes in mobility that might lead to excess falls in people with cancer. Citation Format: Vrutangkumar Shah, Daniel Muzyka, Carolyn Guidarelli, Kristen Sowalsky, Kerri M. Winters-Stone, Fay B. Horak. Chemotherapy-induced peripheral neuropathy and falls in cancer survivors relate to digital balance and gait impairments. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4397.
Abstract 4403: The Efficacy of Immune Checkpoint Inhibitors in Advanced Biliary Tract Cancer with KRAS Mutation
Authors: Sun Young Jeong, Jaeyeon Jang, Youngkyung Jeon, Ye Ji Jung, Daeho Choi, Joohyun Hong, Seung Tae Kim, Jung Yong Hong, Joon Oh Park, Young Suk Park, Ho Yeong Lim
Journal: Cancer Research (2023)

Abstract BackgroundWith a 15% of incidence, KRAS is one of the most common mutations in biliary tract cancer (BTC) and a poor prognostic factor. In BTC, the immune checkpoint inhibitor (ICI) as salvage therapy has modest activity. There was little data on the efficacy of ICIs according to the status of KRAS mutation in BTC. MethodWe conducted molecular profiling in BTC patients who received the ICIs as salvage therapy. Programmed death ligand 1 (PD-L1) expression on tumor cells and tumor-infiltrating lymphocytes (TIL) was also assessed. We analyzed overall survival (OS) and progression-free survival (PFS) of ICI in BTC patients according to the status of PD-L1 expression and KRAS mutation. ResultA total of 62 patients were included in this analysis. The median age was 68.0. 47 patients (75.8%) received pembrolizumab and 15 (24.2%) received nivolumab as salvage therapy. All patients received gemcitabine plus cisplatin as the frontline therapy, and 53.2% had fluoropyrimidine plus oxaliplatin (FOLFOX) before ICIs. The median lines of prior chemotherapy were 2.5. KRAS mutation was found in 14 patients (22.6%). 28 patients (45.2%) were positive for PD-L1 CPS. There was no statistical correlation between the status of KRAS mutation and PD-L1 expression. The median OS and PFS to ICI were 5.6 (IQR; 3.3 - 8.0) and 3.8 (IQR; 3.0 - 4.5) months, respectively. There were no statistically significant differences in PFS to ICIs according to the status of KRAS mutation (Mutant type vs. Wild type) and PD-L1 expression (Positive vs Negative). In subgroup analysis, patients with both KRAS mutation and PD-L1 positivity had longer PFS as compared to patients with KRAS mutation and PD-L1 negativity (6.5 vs 2.6 months, p=0.047). This finding was not shown in patients with a wild type of KRAS. ConclusionThis analysis showed that PD-L1 expression might be a novel biomarker for ICIs in BTC patients with KRAS mutation but not the wild type of KRAS. Citation Format: Sun Young Jeong, Jaeyeon Jang, Youngkyung Jeon, Ye Ji Jung, Daeho Choi, Joohyun Hong, Seung Tae Kim, Jung Yong Hong, Joon Oh Park, Young Suk Park, Ho Yeong Lim. The Efficacy of Immune Checkpoint Inhibitors in Advanced Biliary Tract Cancer with KRAS Mutation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4403.
Abstract 3647: Anti-tumor actions of neutrophils are mediated via STAT5 inhibition
Authors: Sanjana Rajgopal, Massar Alsamraae, Diane Costanzo-Garvey, Leah Cook
Journal: Cancer Research (2023)

Abstract The overall patient survival rate drops dramatically when localized prostate cancer (PCa) progresses to bone metastatic prostate cancer (BM-PCa). The treatment for BM-PCa is limited to palliative therapy, and it is currently incurable. Neutrophils are the most prevalent immune cell in the bone, and we have found that PCa enhances their recruitment and infiltration into the prostate tumor-bone microenvironment of patients with BM-PCa. Additionally, we observed that bone marrow neutrophils directly induce apoptosis of PCa cells both in vitro and in vivo and that this is mediated by the inhibition of STAT5, a transcription factor that promotes PCa progression. Moreover, STAT5 has also been found to contribute to the development of resistance to standard care androgen deprivation therapy. Neutrophils specifically target and kill only cells that express STAT5, as stable knockdown of STAT5 in BM-PCa cells makes them resistant to neutrophil-mediated cytotoxicity, while the overexpression of STAT5 in STAT5-negative PCa cells, which are generally resistant to killing by neutrophils, sensitizes them to neutrophil-mediated killing. Furthermore, transcriptomic analyses derived from the STAT5 knockdown and STAT5 overexpressing cells suggest that STAT5 expression in PCa induces pro-inflammatory signaling and that neutrophil-mediated cytotoxicity may be exerted via STAT5-induced IL-1 and/or IL-6. Preliminary data in our laboratory show that STAT5-induced production of IL-1 by PCa cells leads to their death by neutrophils, as knocking out the IL-1 receptor on neutrophils reduces their cytotoxic potential against STAT5-positive PCa cells. Interestingly, in addition to killing BM-PCa cells, we have demonstrated that bone marrow-derived neutrophils are also capable of killing pancreatic cancer cells. Further delineation of the role of neutrophils in STAT5 signaling in BM-PCa growth holds promise for enhancing neutrophil cytotoxicity in the bone which could lead to novel therapeutic options for bone metastatic prostate cancer. Citation Format: Sanjana Rajgopal, Massar Alsamraae, Diane Costanzo-Garvey, Leah Cook. Anti-tumor actions of neutrophils are mediated via STAT5 inhibition. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3647.
Abstract 3648: MSU-42011, alone and in combination with selumetinib, reduces pERK levels in NF1 cancer cells and decreases <i>CCL2</i> expression in THP-1 macrophages
Authors: Pei-Yu Hung, Lizbeth Lockwood, Karen T. Liby
Journal: Cancer Research (2023)

Abstract Neurofibromatosis type 1 (NF1) is a common genetic disease that predisposes approximately 50% of affected individuals to develop plexiform neurofibromas (PNFs), which can progress to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs) in approximately 10% of patients. NF1 is caused by mutations in the tumor suppressor gene NF1, which encodes for neurofibromin, a negative regulator of RAS activity. Selumetinib, a specific inhibitor of MEK1/2, is the only FDA-approved drug for NF1-associated PNFs. However, the anti-tumor effects of selumetinib are limited in MPNSTs and have dose-limiting side effects. Deficiency of the NF1 gene not only promotes tumorigenesis but also has broad effects on the immune cells and cytokine signaling driven by hyperactive RAS signaling. Because macrophages account for almost half of cells in NF1 lesions and their infiltration highly correlates with disease progression, we hypothesized that targeting tumor-promoting immune cells could be an alternative approach for NF1 treatment. The novel retinoid X receptor (RXR) agonist MSU-42011 reduces tumor growth in experimental Kras-driven cancers by decreasing pERK expression, reducing tumor-promoting immune cells like CD206+ macrophages and regulatory T cells, and increasing activated cytotoxic T cells. Here, we tested MSU-42011 and selumetinib, either alone or in combination, to evaluate their efficacy against NF1 cancer cells and macrophages using monoculture and conditioned media (CM) treatments. Treatment with 200 nM MSU-40211, 50 nM selumetinib, and the combination for 3 hours reduced pERK protein levels by approximately 40%, 70% and 90%, respectively vs. untreated controls. Treatment for 72 hours with selumetinib and the combination reduced the viability of PNF cells in a dose-dependent manner. Moreover, CM from human PNF cells increased monocyte chemoattractant CCL2 (C-C motif chemokine ligand 2) mRNA expression in human THP1 monocytes and THP1 macrophages differentiated by PMA. Notably, MSU-42011 and selumetinib alone similarly inhibited CCL2 mRNA expression by 25% in THP1 macrophages stimulated with CM from PNF cells, and the inhibition of CCL2 mRNA expression was enhanced to 50% with combination treatment. Taken together, our data suggest that MSU-42011 should be tested in relevant preclinical models of NF1. Citation Format: Pei-Yu Hung, Lizbeth Lockwood, Karen T. Liby. MSU-42011, alone and in combination with selumetinib, reduces pERK levels in NF1 cancer cells and decreases CCL2 expression in THP-1 macrophages. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3648.